Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22phox

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1106-1112 ◽  
Author(s):  
Julie Rae ◽  
Deborah Noack ◽  
Paul G. Heyworth ◽  
Beverly A. Ellis ◽  
John T. Curnutte ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Missense Mutation ◽  
Nonsense Mutation ◽  
Granulomatous Disease ◽  
Microbial Infection ◽  
Gene Encoding ◽  
Catalytic Core ◽  
Exon 2 ◽  
Cyba Gene

Chronic granulomatous disease is a rare inherited disorder caused by nonexistent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, NADPH oxidase, involves at least 5 protein components. The absence of, or a defect in, any 1 of 4 of these proteins (p22phox, p47phox, p67phox, or gp91phox) gives rise to the known types of chronic granulomatous disease. One of the rarest forms of the disease is due to defects in the CYBA gene encoding p22phox, which together with gp91phox forms flavocytochromeb558, the catalytic core of NADPH oxidase. To date, only 9 kindreds with p22phoxdeficiency have been described in the literature comprising 10 mutant alleles. Four polymorphisms in the CYBA gene have also been reported. Here we describe 9 new, unrelated kindreds containing 12 mutations, 9 of which are novel. In addition, we report 3 new polymorphisms. The novel mutations are (a) deletion of exons 2 and 3, (b) a missense mutation in exon 3 (T155→C), (c) a splice site mutation at the 5′ end of intron 3, (d) a missense mutation in exon 2 (G74→T), (e) a nonsense mutation in exon 1 (G26→A), (f) a missense mutation in exon 4 (C268→T), (g) a frameshift in exon 3 due to the insertion of C at C162, (h) a nonsense mutation in exon 2 (G107→A), and (i) a missense mutation in exon 2 (G70→A).

Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22phox

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1106-1112 ◽  
Author(s):  
Julie Rae ◽  
Deborah Noack ◽  
Paul G. Heyworth ◽  
Beverly A. Ellis ◽  
John T. Curnutte ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Missense Mutation ◽  
Nonsense Mutation ◽  
Granulomatous Disease ◽  
Microbial Infection ◽  
Gene Encoding ◽  
Catalytic Core ◽  
Exon 2 ◽  
Cyba Gene

Abstract Chronic granulomatous disease is a rare inherited disorder caused by nonexistent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, NADPH oxidase, involves at least 5 protein components. The absence of, or a defect in, any 1 of 4 of these proteins (p22phox, p47phox, p67phox, or gp91phox) gives rise to the known types of chronic granulomatous disease. One of the rarest forms of the disease is due to defects in the CYBA gene encoding p22phox, which together with gp91phox forms flavocytochromeb558, the catalytic core of NADPH oxidase. To date, only 9 kindreds with p22phoxdeficiency have been described in the literature comprising 10 mutant alleles. Four polymorphisms in the CYBA gene have also been reported. Here we describe 9 new, unrelated kindreds containing 12 mutations, 9 of which are novel. In addition, we report 3 new polymorphisms. The novel mutations are (a) deletion of exons 2 and 3, (b) a missense mutation in exon 3 (T155→C), (c) a splice site mutation at the 5′ end of intron 3, (d) a missense mutation in exon 2 (G74→T), (e) a nonsense mutation in exon 1 (G26→A), (f) a missense mutation in exon 4 (C268→T), (g) a frameshift in exon 3 due to the insertion of C at C162, (h) a nonsense mutation in exon 2 (G107→A), and (i) a missense mutation in exon 2 (G70→A).

scholarly journals Chronic granulomatous disease and glutathione peroxidase deficiency, revisited

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3861-3869 ◽  
Author(s):  
PE Newburger ◽  
SE Malawista ◽  
MC Dinauer ◽  
T Gelbart ◽  
RC Woodman ◽  
...  
Keyword(s):  
Glutathione Peroxidase ◽  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Normal Female ◽  
Granulomatous Disease ◽  
Gene Encoding ◽  
Cytochrome B558 ◽  
Peroxidase Enzyme ◽  
Peroxidase Deficiency

We have restudied two kindreds that formed the basis of the original report of autosomal recessive chronic granulomatous disease (CGD) associated with leukocyte glutathione peroxidase deficiency. Case 1 from the original study and the surviving brother of the originally reported case 2 both have severe CGD, with no detectable respiratory burst activity in purified intact neutrophils. However, their leukocytes exhibit normal glutathione peroxidase enzyme activity and gene expression. Examination of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase components known to be defective in CGD reveals no detectable cytochrome b558 nor any membrane activity in a cell-free NADPH oxidase assay system. Molecular analysis of the genes encoding cytochrome b558 subunits shows, in case 1, a C-->T substitution at nucleotide 688 of the gene encoding the gp91-phox subunit of cytochrome b558, resulting in a termination signal in place of Arginine-226. Levels of gp91-phox mRNA are markedly decreased despite normal levels of gene transcription, indicating a post- transcriptional effect of the nonsense mutation on mRNA processing or stability. The X-linked form of CGD developed in this cytogenetically normal female due to the uniform inactivation of the normal X chromosome in her granulocytes, indicated by the expression in her granulocyte mRNA of only one allele of a glucose-6-phosphate dehydrogenase polymorphisms for which she is heterozygous in genomic DNA. Case 2 (of the present study) has distinct mutations in each allele of the p22-phox gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic granulomatous disease caused by mutations other than the common GT deletion inNCF1, the gene encoding the p47phoxcomponent of the phagocyte NADPH oxidase

2006 ◽  
Vol 27 (12) ◽  
pp. 1218-1229 ◽  
Author(s):  
Dirk Roos ◽  
Martin de Boer ◽  
M. Yavuz Köker ◽  
Jan Dekker ◽  
Vinita Singh-Gupta ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Granulomatous Disease ◽  
Gene Encoding ◽  
Phagocyte Nadph Oxidase ◽  
The Common

Autosomal recessive chronic granulomatous disease caused by defects in NCF-1, the gene encoding the phagocyte p47-phox: mutations not arising in theNCF-1 pseudogenes

Blood ◽  
2001 ◽  
Vol 97 (1) ◽  
pp. 305-311 ◽  
Author(s):  
Deborah Noack ◽  
Julie Rae ◽  
Andrew R. Cross ◽  
Beverly A. Ellis ◽  
Peter E. Newburger ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Novel Mutation ◽  
Splice Junction ◽  
Single Mutation ◽  
Missense Mutations ◽  
Granulomatous Disease ◽  
Gene Encoding ◽  
Exon 2 ◽  
Single Defect ◽  
Phagocyte Nadph Oxidase

Abstract Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any one of 4 genes encoding phagocyte NADPH oxidase subunits. Unlike other CGD subtypes, in which there is great heterogeneity among mutations, 97% of affected alleles in patients previously reported with A470 CGD carry a single mutation, a GT deletion (ΔGT) in exon 2 of the p47-phox gene, NCF-1. This unusually high incidence results from recombination events between NCF-1and its highly homologous pseudogenes, in which ΔGT originates. In 50 consecutive patients with A470 CGD, 4 were identified who were heterozygous for ΔGT in NCF-1, and for the first time, 2 were identified whose DNA appeared normal at this position. To avoid co-amplification of pseudogene sequence and to enable the identification of mutations in these patients, allele-specific polymerase chain reaction was used to amplify alleles not containing ΔGT. In each of the 4 patients who were heterozygous for ΔGT, an additional novel mutation was identified. These were 2 missense mutations, G125 → A in exon 2 (predicting Arg42 → Gln) and G784 → A in exon 8 (Gly262 → Ser), and 2 splice junction mutations at the 5′ end of intron 1, gt → at and gtg → gtt. The first of 2 patients who appeared normal at the GT position was a compound heterozygote with the G125 → A transition on one allele and a deletion of G811 on the other. In the second of these patients, only a single defect was detected, G574 → A, which predicts Gly192 → Ser but is likely to result in defective splicing because it represents the final nucleotide of exon 6.

scholarly journals Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease

2016 ◽  
pp. fuw042 ◽  
Author(s):  
Helene Buvelot ◽  
Klara M. Posfay-Barbe ◽  
Patrick Linder ◽  
Jacques Schrenzel ◽  
Karl-Heinz Krause
Keyword(s):  
Staphylococcus Aureus ◽  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Granulomatous Disease ◽  
Phagocyte Nadph Oxidase

scholarly journals Detection of gp91-phox precursor protein in B-cell lines from patients with X-linked chronic granulomatous disease as an indicator for mutations impairing cytochrome b558 biosynthesis

1996 ◽  
Vol 315 (2) ◽  
pp. 571-575 ◽  
Author(s):  
Colin D. PORTER ◽  
KURIBAYASHI KURIBAYASHI ◽  
Mohamed H. PARKAR ◽  
Dirk ROOS ◽  
Christine KINNON
Keyword(s):  
Nadph Oxidase ◽  
B Cell ◽  
Chronic Granulomatous Disease ◽  
Cell Lines ◽  
Binding Domain ◽  
Granulomatous Disease ◽  
Cytochrome B558 ◽  
Stable Association ◽  
P22 Phox ◽  
Fad Binding

NADPH oxidase cytochrome b558 consists of two subunits, gp91-phox and p22-phox, defects of which result in chronic granulomatous disease (CGD). The nature of the interaction between these subunits has yet to be determined. Absence of p22-phox in autosomal CGD patient-derived B-cell lines results in detectable levels of an incompletely glycosylated gp91-phox precursor. We have detected this same precursor species in four cell lines from patients with the X-linked form of the disease due to mutations in gp91-phox. Such mutations should delineate regions of gp91-phox important for its biosynthesis, including stable association with p22-phox. One mutation mapped to the putative FAD-binding domain, one mapped to a potential haem-binding domain, and two involved the region encoded by exon 3.

scholarly journals The p47phox mouse knock-out model of chronic granulomatous disease.

1995 ◽  
Vol 182 (3) ◽  
pp. 751-758 ◽  
Author(s):  
S H Jackson ◽  
J I Gallin ◽  
S M Holland
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Fungal Infections ◽  
Critical Role ◽  
Granulomatous Inflammation ◽  
Mammalian Host ◽  
Granulomatous Disease ◽  
Knock Out ◽  
Phagocyte Nadph Oxidase ◽  
Life Threatening

Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice produced no superoxide and killed staphylococci ineffectively. p47phox-/- mice developed lethal infections and granulomatous inflammation similar to those encountered in human CGD patients. This model mirrors human CGD and confirms a critical role for the phagocyte NADPH oxidase in mammalian host defense.

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